Rare Genetic Diseases and DNA Analysis

Rare Genetic Disease Assessment

• The approach to assessing rare genetic disease involves considering various factors and phenomena
• Factors that influence genetic inheritance include reduced penetrance, variable expressivity, sex effects, de novo variation, pleiotropy, and digenic and polygenic effects

DNA and Genetic Variations

• Human DNA comprises approximately 3 billion base pairs
• The coding region of DNA encompasses 20,000 genes, accounting for 1.5% of the total
• The vast majority of DNA doesn't directly code for proteins

History of DNA Research

• Karyotyping, a technique involving visualizing chromosomes, was introduced in 1956
• The first complete human genome sequence was generated in 2001
• Comparative genomic hybridization (CGH) allows for the identification of genetic changes at the 100kb level
• Next-generation sequencing (NGS) technologies, including whole exome sequencing (WES) and whole genome sequencing (WGS), have revolutionized genetic analysis

Genetic Variation and Disease

• About 99.9% of the human genome is identical between individuals
• The remaining 0.1% accounts for approximately 2-3 million polymorphisms, contributing to phenotypic variations like height and weight
• There are approximately 500 rare missense variants that are commonly found in the population
• Rare variants in known disease genes are estimated to number around 100
• De novo protein-coding mutations are a significant cause of genetic disorders, but they are challenging to detect due to the difficulty in accessing germ cells

The Importance of Genetic Testing

• Genetic testing is becoming increasingly prevalent, driven by advances in technology and improved understanding of genetic variation
• With the discovery of over 7500 genetic disorders since 2012, the role of genetic testing continues to expand.

Understanding Genetic Disease Inheritance

• Mendelian disorders are caused by mutations in a single gene.
• Multifactorial disorders, like high blood pressure, arise from the interplay of genetic and environmental factors
• Genetic heterogeneity refers to the phenomenon where different mutations in multiple genes can cause the same phenotype.
• Incomplete penetrance describes cases where an individual inherits a disease-causing mutation but does not exhibit clinical symptoms.

Key Terminologies in Genetics

• Allele: Alternative forms of a particular gene
• Heterozygous: Having two different alleles at a specific locus
• Homozygous: Having the same alleles at a specific locus
• Hemizygous: Having only one copy of an allele present

Modes of Inheritance

• Dominant inheritance: Heterozygous individuals experience the variant phenotype
• Recessive inheritance: The variant phenotype is only manifest in homozygous individuals (or hemizygous males for X-linked disorders)

Autosomal Dominant Inheritance

• Both males and females can be affected
• Affected individuals typically have an affected parent
• Male-to-male transmission occurs
• There is a 50% chance of passing the disorder from an affected parent to offspring
• Incomplete penetrance can occur, whereby some heterozygotes show no phenotype

Autosomal Recessive Inheritance

• Both males and females are affected
• Parents are usually not affected
• On average, ¼ of offspring are affected
• Consanguinity (closely related family members having children) significantly increases the risk of autosomal recessive disorders

Consanguinity

• First-degree relatives share about 50% of their genes
• Second-degree relatives share about 25% of their genes
• Third-degree relatives share about 12.5% of their genes
• The risk of autosomal recessive disorders increases drastically with increasing levels of consanguinity

De Novo Mutations and Germinal Mosaicism

• De novo mutations are new mutations that occur in germ cells, leading to a genetic disorder without any family history
• Germinal mosaicism refers to the presence of two or more genetically distinct cell lines within an individual's germ cells, which increases the risk of recurrence for de novo mutations

Pleiotropy and Variable Expressivity

• Pleiotropy refers to a single gene affecting multiple seemingly unrelated traits or phenotypes.
• Variable expressivity describes how the severity of a genetic disorder can vary significantly among individuals with the same mutation

Examples of Genetic Disorders

• Achondroplasia is an autosomal dominant disorder caused by mutations in the FGFR3 gene
• Primary Ciliary Dyskinesia (PCD) is an autosomal recessive disorder caused by mutations in genes involved in cilia function
• Tuberous sclerosis is an autosomal dominant disorder caused by de novo mutations in the TSC1 or TSC2 genes